Renal growth and development in mice lacking AT1A receptors for angiotensin II.
To examine the role of the type 1A (AT1A) angiotensin receptor in renal growth and development, we analyzed F2 progeny from a series of crosses between F1 mice that were heterozygous for a targeted disruption of the AT1A receptor gene [Agtr1A-(+/-)]. Among 21-day-old weanling F2 mice, we found that 194 (32%) were homozygous for the wild-type allele Agtr1A-(+/+), 299 (49%) were Agtr1A-(+/-), and 119 (19%) were Agtr1A-(-/-). This differed significantly from the proportions predicted by Mendelian genetics (P = 0.01), suggesting that the complete absence of AT1A receptors is associated with a mild survival disadvantage. Agtr1A-(-/-) mice grew normally, and we found no significant differences in body weight or heart and kidney weights in Agtr1A-(+/+) and Agtr1A-(-/-) mice examined at 21, 60, and 100 days. Protein and DNA content of kidneys and hearts were also similar in weanling or adult Agtr1A-(+/+) and Agtr1A-(-/-) mice. By light microscopy with immunohistochemistry, kidneys from Agtr1A-(-/-) were essentially normal, with two exceptions: 1) there was marked hypertrophy of the juxtaglomerular apparatus (JGA) and proximal expansion of renin-producing cells along the afferent arterioles, and 2) some glomeruli showed evidence of mesangial expansion. We did not find the severe renal vascular lesions or papillary atrophy that have been observed in angiotensinogen- or angiotensin converting enzyme-deficient animals. We conclude that the AT1A receptor is not essential for the normal organogenesis of the kidney; however, its absence is associated with mild mesangial expansion and JGA hypertrophy.
Oliverio
M I
MI
Department of Medicine, Duke University, Durham, North Carolina, USA.
Madsen
K
K
Best
C F
CF
Ito
M
M
Maeda
N
N
Smithies
O
O
Coffman
T M
TM
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001160:Arterioles / Q000473:pathology; D001284:Atrophy; D003433:Crosses, Genetic; D005920:Glomerular Mesangium / Q000473:pathology / Q000648:ultrastructure; D006579:Heterozygote; D006984:Hypertrophy; D007606:Juxtaglomerular Apparatus / Q000473:pathology; D007668:Kidney / Q000166:cytology / Q000254:growth & development* / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency* / Q000235:genetics*; D012079:Renal Circulation; D012083:Renin / Q000096:biosynthesis
D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D012083:Renin